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Laterally spreading tumours (LSTs) of the colon and rectum are defined as lesions greater than 10 mm in diameter with a low vertical axis that extend laterally along the luminal wall.1 As most LSTs remain as adenomas or early invasive cancers, LSTs have been thought to have relatively little malignant potential. LSTs are divided into two macroscopic subtypes: flat (F)-type, which is composed of superficially spreading lesions with flat and smooth surfaces, and granular (G)-type, which is composed of superficially spreading aggregates of nodules.2 Despite distinctive biological behaviours of LSTs, only a few genetic alterations have been reported, such as K-ras and p53 mutations3,4 and cyclooxygenase 2 overexpression.5
A 62 year old Japanese woman was referred to our hospital for treatment of a colonic tumour. Colonoscopy in our hospital showed an F-type LST with a central depression surrounded by a flat elevated area with a smooth surface in the caecum (fig 1A). Microscopically, the tumour consisted of a well differentiated adenocarcinoma with a tubular adenoma and had invaded the submucosal layer.
After obtaining informed consent from the patient, genetic analysis was carried out. No genetic alterations were found in APC, K-ras, or p53 genes. To clarify relevant alterations of gene expression, we analysed the gene expression profiles by a cDNA array.6 Among 550 cancer related genes, bone morphogenic protein 4 (BMP4) was one of the most differentially expressed genes in tumor tissues and matched normal tissues (fig 1B). BMP4 is a member of the transforming growth factor β superfamily of growth factors. As BMP4 expression is reportedly correlated with oncogenic β-catenin in human colon cancer cells,7 we analysed alterations in β-catenin in tumour tissues. Intense nuclear expression of β-catenin was immunohistochemically seen within the nuclei of tumor cells (fig 1C). No point mutations of β-catenin were detected. Interstitial deletion was then examined by polymerase chain reaction. A shorter band was detected in tumor tissues compared with the normal size of 931 base pairs (bp) (fig 1D). DNA sequencing showed an interstitial deletion of 394 bp in tumor tissues (fig 2). Three base inverted repeats, AGC and GCT, were found in the sequences flanking the interstitial deletion. Short nucleotide sequences at both ends of the deletion were complementary, suggesting that inversely repeated sequences were involved in the somatic rearrangements.8 These results suggest that β-catenin deletion played an important role in the early stage of tumorigenesis in the present case. Abnormalities of β-catenin may play a crucial role in the morphological features of LSTs, as β-catenin is involved in cell adhesion. It would be interesting to investigate the frequency of β-catenin and APC alterations in a number of LST cases.
Microsatellite instability (MSI) due to defective DNA mismatch repair occurs in the majority of hereditary non-polyposis colorectal cancers (HNPCC) and in 10–15% of sporadic colorectal cancers. It has been reported that β-catenin mutations occur more often in MSI positive colorectal cancers.9 However, tumor tissues in the present case were MSI negative. Samowitz and colleagues10 reported that β-catenin exon 3 mutations can be an early event in colorectal tumorigenesis. However, Johnson and colleagues9 recently reported that β-catenin exon 3 mutations were rare in small (<1 cm) sporadic adenomas (1/83, 1.2%), HNPCC adenomas (1/37, 2.7%), and in both MSI positive (0/34) and MSI negative (0/78) sporadic colorectal cancers. In contrast, a significantly increased frequency (8/44, 18.2%) was found in HNPCC cancers.9 The present patient had no past history or family history of cancer. It would be interesting to investigate whether β-catenin mutation positive HNPCC cancers have any specific morphological features.
Conflict of interest: None declared.
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